We have shown in a large prospective study of 1,380 patients that psoriatic patients treated with PUVA (orally administered psoralen and subsequent exposure to UVA radiation [365 nm]) develop non-melanoma skin cancer (NMSC) at a greatly increased frequency with markedly decreased latency periods. Prior skin cancer or previous exposure to x-rays further increases the relative risk for PUVA-induced skin cancers. Since detailed PUVA and ionizing radiation exposure histories are available for this well defined population, a unique opportunity exists for the study of exogenously induced carcinogenesis. Heightened susceptibility to cancer may be partly understood by two observations that we have made and that also might help in identifying individuals at risk: first, established cell cultures treated with x-rays show a permanent and heritable hypersensitivity to PUVA-induced mutations; and second, an individual with high numbers of squamous cell carcinomas (SCC) shows certain cytogenetic abnormalities unseen in controls. We also have shown that the populations of cells we will study have been altered by their in vivo exposure to carcinogens, since cells grown from irradiated biopsies senesce at much more rapid rates than cells from unirradiated biopsies from the same individual. We will study skin biopsies from five groups of individuals: (i) psoriasis patients with SCC + prior exposure to PUVA and x-rays; (ii) psoriasis patients with SCC + prior exposure to PUVA only; (iii) patients with exposure to x-ray only; (iv) psoriasis patients without SCC exposed to PUVA; and (v) normal individuals. We will preferentially study those SCC patients with multiple tumors. Biopsies can be taken from both exposed and non-exposed areas of individuals exposed to either or both agents, providing a unique opportunity to distinquish between intrinsic cellular abnormalitites and such changes that result from exposure. Fibroblasts will be grown from skin biopsies to compare several cellular characteristics and responses. We will determine if correlations exist between cellular markers and the documented or predicted susceptibility for cancer. In this way we will evaluate models of multistage carcinogenesis in human skin.